The role of simulator Promis2 in learning laparoscopic skill.

INTRODUCTION: Laparoscopic surgery is unique and complex in nature, so the training is necessary before proceeding to operation room. Many computer aided simulators have been developed for the purpose. Our objective is to assess the improvement of basic laparoscopic skills after training in simulator. METHODS: The fifth year medical students underwent training of three laparoscopic skills using Promis2 simulator twice weekly for 4-6 weeks. The skills are laparoscopic orientation, target pointing and objects transferring. Time, path length of instruments and economy of movements were recorded. The comparisons were made for these parameters between session first and the last using a Mann-Whitney U test. RESULTS: Ten volunteers completed the exercises in less time (186.3 +/- 55.4 seconds) than the first exercise (215.7 +/- 57.4 seconds) (P=0.0027). Both the right and left hand instrument path lengths were also improved from 4425.8 +/- 1284.3 mm in the first exercise to 3925.3 +/- 1313.6 mm in the last exercise in the left side (P=0.0219) and likewise from 4273.8 +/- 1859.4 mm to 3831.3 +/- 1717.4 mm in the right side (P=0.0027). Economy of the movement in the left handed instrument improved from 1114.4 +/- 453.5 mm in the first exercise to 966.8 +/- 411.1 mm in the last (P=0.0443) and in the right handed instrument from 845 +/- 398.8 mm to 771.4 +/- 370.5 mm according to the software of Promis2 simulator (P >0.005). CONCLUSIONS: Training in Promis2 simulator improves the basic laparoscopic skills. The candidates become consistently faster with shorter path lengths and had smoother instruments movements. They also became significantly more consistent in their performance.

Population pharmacokinetics, protein binding and antiarrhythmic effects of disopyramide enantiomers in arrhythmic patients.

Disopyramide (DP) is widely used as an antiarrhythmic agent. The antiarrhythmic effects of its enantiomers differ from each other and its metabolism and protein binding are also stereoselective. Population pharmacokinetic parameters of DP racemate, enantiomers (S(+)-DP, R(-)-DP), and their unbound concentrations (uDP, S(+)-uDP and R(-)-uDP) were analyzed using the nonlinear mixed effect model (NONMEM) program. Data were available from 108 points of 33 arrhythmic patients on maintenance therapy with DP racemate. We evaluated the factors to which pharmacokinetic parameters are attributed and the relationships between each serum concentration and the antiarrhythmic effect. A one-compartment model was fitted to the data using NONMEM. For DP, S(+)-DP and R(-)-DP, elimination rate constants (kes) were estimated as 0.0648, 0.0663 and 0.0691/h, respectively and the mean apparent volume of distribution (Vd/F) were estimated as 63.2, 54.1 and 71.6 l, respectively. Using the ke and Vd/F values estimated by NONMEM, time-concentration curves were well fitted to the observed data. Unbound fractions of both DP enantiomers showed nonlinearity and the binding ratio of S(+)-DP was 0.84 +/- 0.07, which was higher than that of R(-)-DP [0.70 +/- 0.11 (p < 0.01)]. Unbound fractions of both DP enantiomers correlated with alpha1-acid glycoprotein (AGP) (p < 0.01). On the other hand, using NONMEM, a significant proportion of the variability of Vd/F could be attributed only to AGP (p < 0.001). NONMEM was able to clarify the pharmacokinetic features in the protein binding of DP. Individual steady state concentrations were estimated by NONMEM using the Bayesian method. The average unbound concentrations of all nine responders were higher than those of the four non-responders, even though this difference was not significant. Unbound concentrations may reflect drug concentrations in the tissue, which suggests that these concentrations may indicate an antiarrhythmic effect rather than the total concentration.

Influence of age on the pharmacokinetics of vapiprost, a thromboxane A2 receptor antagonist, and platelet aggregation: comparison of pharmacokinetics by routine approach and population pharmacokinetics.

The effects of a single-dose oral administration of a thromboxane A2 receptor antagonist, vapiprost (SN-309), on pharmacokinetic profile and inhibition of platelet aggregation were investigated in six healthy elderly volunteers (age: 65-72 years) and the influence of age on these parameters was studied by comparison with the results obtained in phase-I data involving healthy young participants. Although direct comparison of pharmacokinetic parameters was inappropriate because of different models, high Cmax and AUC values were obtained on comparison with the young. The inhibition of platelet aggregation in platelet rich plasma induced by U-46619 or collagen was rapidly established and remained suppressed for more than 8 h, although the effect was short-acting compared with the inhibition period in the young. This suggests that dose adjustment in the elderly is unnecessary In addition to a routine pharmacokinetic approach to determine the time-profile of vapiprost, population pharmacokinetics were studied using data from 51 volunteers in five clinical trials including the two above-mentioned studies. By fitting 812 plasma-monitoring points into the two-compartment model, the effects of several factors including age on parameters were investigated, based on the nonlinear mixed effect model. Clearance in the elderly attenuated 82.2% of that in the young, the distribution volume varied with platelet counts and delayed absorption was observed in volunteers with, rather than without, food intake. Closer bridging studies with other countries have resulted in the current local situation of abbreviating phase-III studies. Consequently to clarify the pharmacokinetic profile of the elderly in Japan and other countries, the population pharmacokinetics approach based on the data in the various phase I-II trials is useful.

[Pharmacokinetic studies of menogaril (TUT-7) with rats].

Menogaril (TUT-7) is a novel antitumor antibiotic belonging to anthracyclines. The pharmacokinetic parameters derived from plasma concentration-time profiles after repeated (for 14 days) or single oral administration of TUT-7 to rats were found to be not significantly different by either administration schedule. The rats with artificial liver dysfunction were obtained by subcutaneous application of carbon tetrachloride (CCl4, 1 ml/kg) for 3 days. After oral administration of TUT-7 to the rats with CCl4-induced liver toxicity (3 daily administrations of 1mg/kg, S.C.), the maximum plasma concentrations (Cmax) and AUC of both the unchanged drug and its metabolite N-Demethyl menogaril, were increased. Also over all elimination was slower in animals with liver dysfunction.

WBN/Kob rats. A new spontaneously occurring model of chronic pancreatitis.

Chronic pancreatitis-like lesions are observed in 100% of male Wistar Bonn/Kobori rats. At 3 mo of age, histopathologic examinations of the pancreas revealed a distinct infiltration of inflammatory cells with interstitial edema in the acini. At the same time, periductal and interstitial fibrosis and adenomatous hyperplasia of the ductular epithelium were observed. Extensive fibrotic exudation developed rapidly with age, and irregular destruction of the parenchyma was noted. The only abnormality, prior to the appearance of glycosuria, that could be detected clinically was lower levels, compared to Wistar rats, of BT-PABA excreted in the urine after oral ingestion. These lower levels indicate a decrease in enzyme secretion in WBN/Kob rats. Ultrastructural observations in histologically normal areas at 2 mo of age showed a swelling of mitochondria, indicating that ischemia was associated with the early pancreatic lesions. Serial pancreatographies were performed at 2-8 mo of age. Irregular widenings of the main pancreatic duct and dilations of the smaller ducts were observed already at 2 mo of age, suggesting a stasis of pancreatic juice in the early stages of the disease. It seems that male WBN/Kob rats are a useful model of human chronic pancreatitis, with an unknown mechanism regulated by the sex hormones.